Pharmacokinetics, Pharmacodynamics, Safety, and Tolerability of Oral AL01211 in Healthy Chinese Volunteers.

2024-05-02
Clinical drug investigation 44(6)
- Lei Dong
- Jianxing Xiang
- Michael Babcock
- Yuanzhi Cheng
- Yan Wang
- Yuqiao Shen
- Li Li
- Liping Tan
- Marvin Garovoy
- Wei Hu
- Jianhong Zheng

PubMed: 38698285
DOI: 10.1007/s40261-024-01362-2

Study Design

Type: Randomized Controlled Trial (RCT)
Population: healthy Chinese volunteers
Methods: Phase 1, single-center, randomized, double-blind, placebo-controlled study with single-dose (15 and 60 mg) and multiple-dose (30 mg) arms
Blinding: Double-blind
Duration: 14 days
Funding: Unclear

Background and objective

Aberrant accumulation of glycosphingolipids (GSLs) in the lysosome leads to GSL storage diseases. Glucosylceramide synthase inhibitors (GCSi) have the potential to treat several GSL storage diseases by reducing the synthesis of the disease-causing GSLs. AL01211 is a potent oral GCSi under investigation for Type 1 Gaucher disease and Fabry disease. Here, we evaluate the pharmacokinetics, pharmacodynamics, safety, and tolerability of AL01211 in healthy Chinese volunteers.

Methods

AL01211 was tested in a Phase 1, single-center, randomized, double-blind, placebo-controlled study with single-dose (15 and 60 mg) and multiple-dose (30 mg) arms.

Results

Results of AL01211 demonstrated dose-dependent pharmacokinetics, rapid absorption (median time to maximum plasma concentration [t_max] 2.5-4 hours), relatively slow clearance rate (mean apparent total clearance from plasma [CL/F] 88.3-200 L/h) and the mean terminal half-life above 30 hours. Repeated once-daily oral administration of AL01211 for 14 days had an approximately 2-fold accumulation, reaching steady-state levels between 7 and 10 days, and led to a 73% reduction in plasma glucosylceramide (GL1) on Day 14. AL01211 was safe and well tolerated, with no identified serious adverse events.

Conclusion

AL01211 showed a favorable pharmacokinetic, pharmacodynamics, safety, and tolerability profile in healthy Chinese volunteers. These data support the further clinical development of AL01211 as a therapy for GSL storage diseases.

Clinical trial registry

Clinical Trial Registry no. CTR20221202 ( http://www.chinadrugtrials.org.cn ) registered on 6 June 2022 and ChiCTR2200061431 ( http://www.chictr.org.cn ) registered on 24 June 2022.